US8232309B2ExpiredUtilityPatentIndex 61
Prodrugs of compounds that inhibit TRPV1 receptor

Assignee: GOMTSYAN ARTHUR RPriority: Oct 28, 2005Filed: Oct 27, 2006Granted: Jul 31, 2012
Est. expiryOct 28, 2025(expired)· nominal 20-yr term from priority
Inventors:GOMTSYAN ARTHUR R BAYBURT EROL K KOENIG JOHN R MARSH KENNAN C SCHMIDT JR ROBERT G LEE CHIH-HUNG WANG WEILI DAANEN JEROME F BROWN BRIAN S
A61P 43/00A61P 25/00A61P 25/04A61P 29/00A61P 13/02C07D 405/12C07D 403/12A61P 13/00C07F 9/65038A61P 13/10C07D 231/56A61K 31/416C07D 407/12
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Claims
Abstract

Compounds of formula (I) wherein A, R 1 , R 2 , and R 3 are defined in the specification, and which are useful as therapeutic compounds particularly for treating disorders or conditions associated with inflammation, pain, bladder overactivity, urinary incontinence, and other disorders caused by or exacerbated by TRPV1.
Claims

exact text as granted — not AI-modified
1. A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, salt of a prodrug or a combination thereof, wherein
 A is cyclopently 
 
       
         
           
           
               
               
           
         
         R 1  is alkyl, cycloalkyl, alkenyl, halogen or haloalkyl; 
         R 2  is hydrogen; 
         R 3  is 
       
       
         
           
           
               
               
           
         
         wherein
 R 4  is —C(O)—O—(CH 2 ) m R 5 , —C(O)(CH 2 ) n —R 6 , —(CH 2 ) r —R 7 , —C(O)R 8 , or —CH 2 (H)(OH)R 9 ; 
 
         m is 1, 2, or 3; 
         n is 1, 2 or 3; 
         r is 1, 2 or 3; 
         t is 0, 1, 2, 3 or 4; 
         u is 0, 1, 2 or 3; 
         R 5  is —O—P(O)(OR A )(OR A ), —P(O)(OR A )(OR A ), —OR A , —OC(O)(R A ), heterocycle, —C(O)OR A , —C(O)N(R B ) 2 , —C(O)(R A ), —NR A R B , or —N(R B )C(O)OR A , 
         R 6  is —OC(O)(R A ), —OR A , —C(O)OR A , —NR A R B , —OP(O)(OR A )(OR A ), or —P(O)(OR A )(OR A ); 
         R 7  is heterocycle, —OC(O)(R A ), —OC(O)(hydroxyalkyl), —OP(O)(OR A )(OR A ), or —P(O)(OR A )(OR A ), 
         R 8  is heterocycle or N(R 8a )(R 8b ) wherein R 8a  and R 8b  are independently hydrogen or alkyl; 
         R 9  is alkoxyalkyl, —C(O)OR A , -alkyl-N(R B )C(O)OR A , or heterocyclealkyl; 
         R A  is hydrogen, alkyl, alkoxyalkyl, aryl or arylalkyl; 
         R B  is hydrogen or alkyl; 
         the heterocycle and the heterocycle moiety of the heterocyclealkyl, represented by R 5 , R 7 , R 8 , and R 9 , are each independently substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, —C(O)OH, -alkyl-C(O)OH, and —N(Z A )(Z B ); 
         Z A  and Z B  are each independently hydrogen, alkyl, —C(O)alkyl, formyl, aryl, or arylalkyl; and 
         the aryl and the aryl moiety of the arylalkyl, represented by R A , Z A  and Z B  are each independently substituted with 0, 1, 2 or 3 substituents selected from the group consisting of alkyl, haloalkyl, alkoxy and haloalkoxy. 
       
     
     
       2. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, alkenyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —(CH 2 ) r —R 7 . 
       
     
     
       3. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —C(O)(CH 2 ) n —R 6 . 
       
     
     
       4. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —CH 2 C(H)(OH)R 9 . 
       
     
     
       5. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —C(O)R 8 . 
       
     
     
       6. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is heterocyclealkyl; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —C(O)—O—(CH 2 ) m R 5 . 
       
     
     
       7. The compound of  claim 6 , wherein
 R 5  is —O—P(O)(OR A )(OR A ). 
 
     
     
       8. The compound of  claim 6  wherein
 R 5  is —P(O)(OR A )(OR A ). 
 
     
     
       9. The compound of  claim 6  wherein
 R 5  is —OR A . 
 
     
     
       10. The compound of  claim 6  wherein
 R 5  is —OC(O)(R A ). 
 
     
     
       11. The compound of  claim 6  wherein
 R 5  is heterocycle. 
 
     
     
       12. The compound of  claim 6  wherein
 R 5  is —C(O)OR A . 
 
     
     
       13. The compound of  claim 6  wherein
 R 5  is selected from the group consisting of —C(O)R A , —N(R B )C(O)OR A , —NR A R B , and —C(O)N(R B ) 2 . 
 
     
     
       14. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —C(O)R 8 . 
       
     
     
       15. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is —CH 2 C(H)(OH)R 9 . 
       
     
     
       16. The compound of  claim 1 , wherein
 R 1  is alkyl, cycloalkyl, halogen or haloalkyl; 
 R 2  is hydrogen; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  is selected from the group consisting of —C(O)—O—(CH 2 ) m R 5 , —C(O)(CH 2 ) n —R 6 , and —(CH 2 ) r —R 7 . 
       
     
     
       17. A compound selected from the group consisting of
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-morpholin-4-ylethyl)-1H-indazol-4-yl]urea; 
 2-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-oxoethyl acetate; 
 N-{1-[(benzyloxy)acetyl]-1H-indazol-4-yl}-N′-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(methoxyacetyl)-1H-indazol-4-yl]urea; 
 4-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-4-oxobutanoic acid; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea trifluoroacetic acid salt; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-(1-glycoloyl-1H-indazol-4-yl)urea; 
 5-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-5-oxopentanoic acid; 
 2-(phosphonooxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(benzyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-hydroxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-[(di-tert-butoxyphosphoryl)oxy]ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 3-(benzyloxy)propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 3-hydroxypropyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 3-[(di-tert-butoxyphosphoryl)oxy]propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 3-(phosphonooxy)propyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(hydroxymethyl)-1H-indazol-4-yl]urea; 
 {4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}methyl acetate; 
 {4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}methyl 3-hydroxypropanoate; 
 {[bis(benzyloxy)phosphoryl]oxy}methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 (phosphonooxy)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 dibenzyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-3-oxopropyl phosphate; 
 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-3-oxopropyl dihydrogen phosphate; 
 [bis(benzyloxy)phosphoryl]methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid triethylamine salt; 
 2-methoxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 (2-oxo-1,3-dioxolan-4-yl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(benzyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-hydroxyethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(benzyloxy)-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-{[(benzyloxy)carbonyl]amino}ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]acetic acid; 
 2-aminoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate hydrochloride; 
 2-ethoxy-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 (diethoxyphosphoryl)methyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(diethylamino)-2-oxoethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-oxopropyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(acetyloxy)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 2-(dimethoxyphosphoryl)ethyl 4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, diethylaminoethanol salt; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, triethanolamine salt; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, piperazine salt; 
 [({4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}carbonyl)oxy]methylphosphonic acid, N-methyl-D-glucamine salt; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-hydroxy-3-methoxypropyl)-1H-indazol-4-yl]urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[2-(2-hydroxy-3-methoxypropyl)-2H-indazol-4-yl]urea; 
 methyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropanoate; 
 methyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-2H-indazol-2-yl}-2-hydroxypropanoate; 
 tert-butyl 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropylcarbamate; 
 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazol-1-yl}-2-hydroxypropanoic acid; 
 3-{4-[({[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-2H-indazol-2-yl}-2-hydroxypropanoic acid; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[2-(2-hydroxy-3-morpholin-4-ylpropyl)-2H-indazol-4-yl]urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(2-hydroxy-3-morpholin-4-ylpropyl)-1H-indazol-4-yl]urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-{1-[(4-methylpiperazin-1-yl)carbonyl]-1H-indazol-4-yl}urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-{2-[(4-methylpiperazin-1-yl)carbonyl]-2H-indazol-4-yl}urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea; 
 N-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-N′-[1-(N,N-dimethylglycyl)-1H-indazol-4-yl]urea, hydrochloride salt; 
 ((R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(2-methoxyethoxy)acetyl)-1H-indazol-4-yl)urea; 
 1-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(3,5,5-trimethylhexanoyl)-1H-indazol-4-yl)urea; 
 2-ethylhexyl 4-(3-((R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-carboxylate; 
 (R)-1-(1-(2-(2-butoxyethoxy)acetyl)-1H-indazol-4-yl)-3-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)urea; 
 3-(dimethylamino)propyl 4-(3-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)ureido)-1H-indazole-1-carboxylate; 
 1-(4-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea trifluoroacetate; 
 1-(5-cyclopropyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride; 
 1-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)-3-(4-(3,3-dimethylbutyl)-5-fluoro-2,3-dihydro-1H-inden-1-yl)urea; 
 (R)-1-(4-cyclopropyl-5-fluoro-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(dimethylamino)acetyl)-1H-indazol-4-yl)urea; and 
 (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1-(2-(methylamino)acetyl)-1H-indazol-4-yl)urea hydrochloride; 
 
     
     
       18. A pharmaceutical composition comprising a therapeutically effective amount of one or more compound of formula (I) as described in  claim 1 , or a therapeutically acceptable salt thereof, or combination thereof, and a pharmaceutically acceptable carrier. 
     
     
       19. A method of treating neuropathic pain, inflammatory pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       20. A method of treating thermal hyperalgesia, bladder overactivity or urinary incontinence, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
       21. The compound of  claim 1  of formula (II), 
       
         
           
           
               
               
           
         
       
     
     
       22. The compound of  claim 1  of formula (III),
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